Novel TSHR Germline Mutation (Met463Val) Masquerading as Graves' Disease in a Large Welsh Kindred with Hyperthyroidism

Abstract

Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin (TSH) receptor (TSHR) gene. We describe an extended Welsh kindred with toxic thyroid hyperplasia affecting 8 family members in three generations and a history consistent with thyrotoxicosis in a further three generations now deceased. A novel heterozygous germline mutation (ATG --> GTG; Met463Val) was identified in the second membrane spanning TSHR region in 6 relatives with thyrotoxicosis and goiter and absence of TSHR antibodies. Screening of 5 additional family members led to the identification of 2 siblings with the mutation, who were asymptomatic at the time, although subsequent thyroid function tests in these children showed suppressed serum TSH and increased serum free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. Functional studies of the novel TSHR germline mutation demonstrated a constitutive activation of the cAMP pathway, which in the thyroid controls both thyroid hormone production and stimulation of thyroid growth. The molecular diagnosis in this family has clinical implications: genetic counseling is required, and primary thyroid ablation should be advocated as the preferred treatment in the patients with the constitutively activating TSHR germline mutation.

A Novel Thyrotropin Receptor Germline Mutation (Asp617Tyr) Causing Hereditary Hyperthyroidism

“…Therefore, it is likely that the grandfather might harbor this mutation but showed no history of hyperthyroidism throughout his life. While previous reports showed that nonautoimmune hyperthyroidism was complicated with chronic thyroiditis in several cases [8,14,31], our data indicate that the clinical picture of the affected member 6 was complicated by autoimmune Graves' disease. Constitutively activating TSHR germline mutations have been predominantly identified in TMs but have also been identified in connecting intracellular and extracellular loops (Table 3).…”

“…Subsequently, 29 germline TSHR mutations in 19 families [1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] and 10 individuals with sporadic occurrence [19,20] were reported. Clinical characteristics in familial cases include: autosomal dominant transmission, hyperthyroidism with a variable age of onset, hyperplastic goiter of variable size, and absence of clinical or biological features of autoimmunity [1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Even among family members harboring the same mutation, clinical features are variable, suggesting that environmental factors including iodine intake, or other genetic factors may be required for full expression of the phenotype.…”

Demonstration of reduced in vivo surface expression of activating mutant thyrotrophin receptors in thyroid sections

“…A number of studies have applied a variety of TSHR antibodies in flow cytometry analysis of surface expression of various mutant TSHR, including the mutants examined in the present work (23,24,29,30). The antibodies used have been predominantly BA8 and 3G4/2C11, the former recognises conformation and the latter two a linear epitope in the ECD of the TSHR.…”

A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

“…To date, ~30 constitutively activating TSHR mutations have been reported in nonautoimmune hyperthyroidism (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(15)(16)(17)(18)(19). Most of the activating mutations are present in TMD 1, 2, 3, and 5.…”

“…Activating germline mutations of TSHR cause nonautoimmune sporadic congenital hyperthyroidism or familial nonautoimmune hyperthyroidism (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). To date, gain-of-function mutations in TMD 1, 2, 3, 5, 6, and 7 and in the ECD have been reported (4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”